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Παρασκευή 20 Οκτωβρίου 2017

Everolimus in advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors: RADIANT-4 lung subgroup analysis

Summary

In the phase 3, RADIANT-4 study, everolimus improved median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated (grade 1 or grade 2), nonfunctional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.35-0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT-4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, = 63 and placebo, = 27). Median PFS (95% CI) by central review was 9.2 (6.8-10.9) months in everolimus arm vs 3.6 (1.9-5.1) months in placebo arm (HR, 0.50; 95% CI, 0.28-0.88). More patients who received everolimus (58%) experienced any tumor shrinkage compared with placebo (13%). Most frequently reported (≥ 5% incidence) grade 3-4 drug-related adverse events (everolimus vs placebo) included stomatitis (11% vs 0%), hyperglycemia (10% vs 0%), and any infections (8% vs 0%). In patients with advanced, progressive, well-differentiated, nonfunctional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT-4 population. These results support the use of everolimus in patients with advanced, nonfunctional lung NET.

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HIF-1α Promotes Breast Cancer Cell MCF-7 Proliferation and Invasion Through Regulating miR-210

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 297-301.


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PERK-Phosphorylated eIF2α Pathway Suppresses Tumor Metastasis Through Downregulating Expression of Programmed Death Ligand 1 and CXCL5 in Triple-Negative Breast Cancer

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 282-287.


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An Overview of Unfolded Protein Response Signaling and Its Role in Cancer

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 275-281.


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Imaging of Integrin αvβ3 Expression in Lung Cancers and Brain Tumors Using Single-Photon Emission Computed Tomography with a Novel Radiotracer 99mTc-IDA-D-[c(RGDfK)]2

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 288-296.


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Low Concentration of 5-Fluorouracil Increases the Effectiveness of Tumor RNA to Activate Murine Dendritic Cells

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 302-308.


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First Clinical Trial Combining Focused Ultrasound and an Immuno-Oncology Drug Begins for Breast Cancer

A ground-breaking clinical trial for women diagnosed with stage IV metastatic breast cancer is now enrolling patients at the University of Virginia Health System.


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Lateral hypothalamic activity indicates hunger and satiety states in humans

Abstract

Lateral hypothalamic area (LHA) local field potentials (LFPs) were recorded in a Prader–Willi patient undergoing deep brain stimulation (DBS) for obesity. During hunger, exposure to food-related cues induced an increase in beta/low-gamma activity. In contrast, recordings during satiety were marked by prominent alpha rhythms. Based on these findings, we have delivered alpha-frequency DBS prior to and during food intake. Despite reporting an early sensation of fullness, the patient continued to crave food. This suggests that the pattern of activity in LHA may indicate hunger/satiety states in humans but attest to the complexity of conducting neuromodulation studies in obesity.



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Network modeling of kinase inhibitor polypharmacology reveals pathways targeted in chemical screens.

http:--journals.plos.org-plosone-resourc Related Articles

Network modeling of kinase inhibitor polypharmacology reveals pathways targeted in chemical screens.

PLoS One. 2017;12(10):e0185650

Authors: Ursu O, Gosline SJC, Beeharry N, Fink L, Bhattacharjee V, Huang SC, Zhou Y, Yen T, Fraenkel E

Abstract
Small molecule screens are widely used to prioritize pharmaceutical development. However, determining the pathways targeted by these molecules is challenging, since the compounds are often promiscuous. We present a network strategy that takes into account the polypharmacology of small molecules in order to generate hypotheses for their broader mode of action. We report a screen for kinase inhibitors that increase the efficacy of gemcitabine, the first-line chemotherapy for pancreatic cancer. Eight kinase inhibitors emerge that are known to affect 201 kinases, of which only three kinases have been previously identified as modifiers of gemcitabine toxicity. In this work, we use the SAMNet algorithm to identify pathways linking these kinases and genetic modifiers of gemcitabine toxicity with transcriptional and epigenetic changes induced by gemcitabine that we measure using DNaseI-seq and RNA-seq. SAMNet uses a constrained optimization algorithm to connect genes from these complementary datasets through a small set of protein-protein and protein-DNA interactions. The resulting network recapitulates known pathways including DNA repair, cell proliferation and the epithelial-to-mesenchymal transition. We use the network to predict genes with important roles in the gemcitabine response, including six that have already been shown to modify gemcitabine efficacy in pancreatic cancer and ten novel candidates. Our work reveals the important role of polypharmacology in the activity of these chemosensitizing agents.

PMID: 29023490 [PubMed - indexed for MEDLINE]



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Dual AAV Gene Therapy for Duchenne Muscular Dystrophy with a 7-kb Mini-Dystrophin Gene in the Canine Model

Human Gene Therapy , Vol. 0, No. 0.


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Using oncology real-world evidence for quality improvement and discovery: the case for ASCO's CancerLinQ

Future Oncology, Ahead of Print.


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Denosumab for the treatment of bone disease in solid tumors and multiple myeloma

Future Oncology, Ahead of Print.


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Advanced diagnostic endoscopy in lower GI: A review of JGES Core Sessions

Abstract

At the 89th –92nd Congress of the Japan Gastroenterological Endoscopy Society, a series of featured discussion sessions concerning advanced diagnostic endoscopy in the lower gastrointestinal tract were presented each year. In total 45 lectures were presented in regard to this subject area. It was revealed that several convenient and less invasive colonoscopic modalities have been developed in recent years. This review article summarizes these core sessions and the efficacy of the techniques discussed.

This article is protected by copyright. All rights reserved.



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A multicenter prospective evaluation study of endoscopic ultrasound-guided hepaticogastrostomy combined with antegrade stenting (with video)

Abstract

Objective

EUS-guided hepaticogastrostomy (EUS-HGS) is often indicated for advanced stage patients because it prevents the adverse events associated with EUS-HGS procedures, and provides long stent patency.

EUS-guided antegrade stenting (AS) has been developed as an advanced technique. Thus, to prevent adverse events and achieve, long stent patency, EUS-AS combined with EUS-HGS (EUS-HGAS) has been reported. The aim of this study was to evaluate the technical feasibility and efficacy of EUS-HGAS in a multicenter, prospective study.

Methods

This prospective study was carried out at each hospital of the Therapeutic endoscopic ultrasound group. The primary endpoint of this multicenter prospective study was the stent patency of EUS-HGAS.

Results

A total of 49 patients were enrolled. The technical success rate of EUS-HGS was 95.8% (47/49). EUS-AS failed in 5 patients because the guidewire could not be advanced into the intestine across the bile duct obstruction site. Therefore, EUS-HGAS was successfully performed in 40 patients (technical success rate: 85.7%). Median overall survival was 114days. Median stent patency including stent dysfunction and patient's death was 114days. On the other hand, mean stent patency was 320 days. Adverse events were seen in 10.2% (5/49) of cases. Hyperamylasemia was seen in 4patients, and bleeding was seen in 1 patient.

Conclusions

In conclusions, the present study is the first to evaluate EUS-HGAS. EUS-HGAS has clinical benefit for obtaining long stent patency, and avoiding adverse events, although the possibility of acute pancreatitis due to obstruction of the orifice of the pancreatic duct must be considered.

This article is protected by copyright. All rights reserved.



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Endoscopic reduction of gastric antrum herniation through the foramen of Winslow into the lesser sac

Abstract

A 67-years-old woman visited our hospital because of abdominal distension and vomiting. Upper gastrointestinal series (UGI) showed diffuse stomach dilatation with no contrast passage (Fig. 1a). Abdominal computed tomography(CT) scan revealed entrapment of the antrum and converging mesenteric vessels into the lesser sac through Winslow's foramen without evidence of bowel necrosis or strangulation (Fig. 1b).

This article is protected by copyright. All rights reserved.



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Association of the HLA-B alleles with carbamazepine-induced Stevens–Johnson syndrome/toxic epidermal necrolysis in the Javanese and Sundanese population of Indonesia: the important role of the HLA-B75 serotype

Pharmacogenomics, Ahead of Print.


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A noninterventional, multicenter, prospective phase IV study of trabectedin in patients with advanced soft tissue sarcoma

imageThis prospective, noninterventional study is the first phase IV trial designed to evaluate trabectedin in patients with advanced soft tissue sarcoma in real-life clinical practice across Europe. To be included in the study, patients must have received more than or equal to one cycle of trabectedin and be currently on treatment. The primary endpoint was progression-free survival as defined by investigators. The secondary endpoints included objective response rate, disease control rate, time to progression and the growth modulation index (GMI), overall survival, and an assessment of the cancer-related symptoms and safety. A total of 218 patients from 41 European centers were evaluated. Patients received a median of six cycles per patient, mostly on an outpatient basis (n=132; 60.6%). The median progression-free survival was 5.9 months, with 70 and 49% of patients free from progression at 3 and 6 months after treatment, respectively. Three (1.4%) patients achieved a complete response and 55 (25.2%) patients achieved a partial response for an objective response rate of 26.6%. A total of 85 (39.0%) patients had disease stabilization for a disease control rate of 65.6%. The median GMI was 0.8, with 5.1 and 38.8% of patients with a GMI of greater than 1.1 to less than 1.33 and greater than or equal to 1.33, respectively. The median overall survival was 21.3 months. Febrile neutropenia (2.3% of patients), neutropenia, nausea, and pneumonia (1.4% each) were the most common trabectedin-related grade 3/4 serious adverse drug reactions. Trabectedin confers clinically meaningful long-term benefits to patients with multiple soft tissue sarcoma histotypes, being either comparable or better than those observed previously in clinical trials, and with a manageable safety profile.

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Two faces of Hippo: activate or suppress the Hippo pathway in cancer

imageThe Hippo pathway has generated considerable interest in recent years because of its involvement in several key hallmarks of cancer progression and metastasis. Research on the Hippo signaling pathway in cancer has been used to determine the activity of yes-associated protein (YAP) in tumorigenesis and disease progression. Previous studies have shown that the Hippo pathway can be used as a target to inhibit YAP activity and is a viable treatment for cancer. However, more studies are required to further advance our understanding of the Hippo signaling pathway in cancer. It has been shown that knockout of serine/threonine-kinases LATS1/2 in the Hippo pathway suppresses cancer immunity in mice. In addition, suppression of the oncogene YAP could contribute toward cancer immune therapy. Therefore, regulation of Hippo signaling can be an attractive alternative strategy for cancer treatment. This review will provide a summary of currently known compounds that activate or suppress the Hippo pathway.

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Extended topoisomerase 1 inhibition through liposomal irinotecan results in improved efficacy over topotecan and irinotecan in models of small-cell lung cancer

imageLiposomal irinotecan (irinotecan liposome injection, nal-IRI), a liposomal formulation of irinotecan, is designed for extended circulation relative to irinotecan and for exploiting discontinuous tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite, SN-38. Sustained inhibition of topoisomerase 1 by extended SN-38 exposure as a result of delivery by nal-IRI is hypothesized to enable superior antitumor activity compared with traditional topoisomerase 1 inhibitors such as conventional irinotecan and topotecan. We evaluated the antitumor activity of nal-IRI compared with irinotecan and topotecan in preclinical models of small-cell lung cancer (SCLC) including in a model pretreated with carboplatin and etoposide, a first-line regimen used in SCLC. Nal-IRI demonstrated antitumor activity in xenograft models of SCLC at clinically relevant dose levels, and resulted in complete or partial responses in DMS-53, DMS-114, and NCI-H1048 cell line-derived models as well as in three patient-derived xenograft models. The antitumor activity of nal-IRI was superior to that of topotecan in all models tested, which generally exhibited limited control of tumor growth and was superior to irinotecan in four out of five models. Further, nal-IRI demonstrated antitumor activity in tumors that progressed following treatment with topotecan or irinotecan, and demonstrated significantly greater antitumor activity than both topotecan and irinotecan in NCI-H1048 tumors that had progressed on previous carboplatin plus etoposide treatment. These results support the clinical development of nal-IRI in patients with SCLC.

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miR-449a: a potential therapeutic agent for cancer

imageMicroRNAs (miRNAs) have been reported to be associated with cancer progression and carcinogenesis. They are small, highly conserved, noncoding RNA molecules consisting of 19–25 nucleotides. By binding to complementary binding sites within the 3′-untranslated region of target mRNAs, miRNAs inhibit the translation of mRNAs or promote their degradation. miRNAs play critical roles in cancer initiation and development by functioning either as oncogenes or as tumor suppressors. Similarly, several studies have shown that miRNAs are involved in regulating various biological processes, including apoptosis, proliferation, cellular differentiation, signal transduction, and carcinogenesis. Among miRNAs, one that may be of particular interest in cancer biology is miR-449a, which has been reported to inhibit tumor growth, invasion, and metastasis, and to promote apoptosis and differentiation through the transforming growth factor-β activated kinase 1, NOTCH, nuclear factor-κB/P65/vascular endothelial growth factor, retinoblastoma-E2F, mitogen-activated protein kinase signaling pathways, WNT–β-catenin signaling, tumor protein P53, and androgen receptor signaling pathways. The miR-449 cluster is located in the second intron of CDC20B on chromosome 5q11.2, a region that has been identified as a susceptibility locus in cancer, and the abnormal expression of miR-449a may be related to the occurrence and development of tumors. As one example, miR-449a has been reported to be involved in the development of carcinoma and may be a potential prognostic indicator. On the basis of the putative pathogenetic relationships between cancer and miR-449a, we consider that miR-449a has the potential to serve as a therapeutic agent for the treatment of some types of cancer. In this review, the role of miR-449a in tumorigenesis and its mechanism of action are explored. Furthermore, its potential as a therapeutic agent in cancer treatment is considered.

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N1-guanyl-1,7-diaminoheptane enhances the chemosensitivity of acute lymphoblastic leukemia cells to vincristine through inhibition of eif5a-2 activation

imageN1-guanyl-1,7-diaminoheptane (GC7), a deoxyhypusine synthase inhibitor, has been shown to exert antiproliferation effects in many solid tumors by regulating eukaryotic translation initiation factor 5a2 (eif5a-2). However, little is known about the role of GC7 and eif5a-2 in drug resistance in acute lymphoblastic leukemia (ALL). In the present study, we investigated the effect of GC7 on drug-resistant ALL and its potential mechanism. We found that using the CCK-8 assay that combined treatment with GC7 and vincristine (VCR) significantly inhibited the cell viability of two ALL cell lines. Using EdU incorporation assays and flow cytometry, we also showed that GC7 could markedly enhance the VCR sensitivity of ALL cells by suppressing cell proliferation and promoting apoptosis. Furthermore, we showed that GC7 could downregulate eif5a-2 and myeloid cell leukemia-1 (Mcl-1) expression. Knockdown of eif5a-2 inhibited the expression of Mcl-1 and significantly enhanced the VCR sensitivity. Moreover, eif5a-2 knockdown decreased the regulatory role of GC7 in increasing VCR sensitivity. Thus, our findings indicate that combined treatment with GC7 could enhance VCR sensitivity of ALL cells by regulating the eif5a-2/Mcl-1 axis. Together, our results highlight the potential clinical application of GC7 in VCR-based chemotherapy for the treatment of ALL.

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A novel hydroxyphenyl hydrazone derivate YCL0426 inhibits cancer cell proliferation through sequestering iron

imageCancer cells have an increased requirement for iron than normal cells, and iron chelators are under active consideration for cancer treatment. The metal-sequestering potential and antiproliferative mechanisms of a novel hydroxyphenyl hydrazone derivate YCL0426 were investigated here. Antiproliferative activity of YCL0426 was detected by MTT assay. The iron-sequestering potential was evaluated by ferrozine–Fe(II) sequestering assay and Fe(II) titration assay. Cell-cycle-arresting profile was checked by flow cytometry and the DNA synthesis status was evaluated by BrdU incorporation assay. SW480 cells stably expressing Rad51-EGFP fusion protein were used to evaluate the DNA damaging potential of the compound. The impact of extra Fe(II) supplement on compound activities was also examined. YCL0426 shows significant antiproliferative activity on 15 cancer cell lines with mean IC50 values of 5.25 μmol/l. YCL0426 displayed concentration-dependent Fe(II) sequestering ability in ferrozine–Fe(II) sequestering assay, and induced upregulation of transferrin receptor 1 and divalent metal transporter 1 expression in HepG2 cells, which are genes responsible for Fe(II) uptake. YCL0426 blocked DNA synthesis in BrdU incorporation assay, and arrested cell cycle at S or G1 phase. Besides, YCL0426 induced Rad51 foci formation and histone H2AX phosphorylation with EC50 values of 1.35 and 2.29 μmol/l, respectively, indicating the emergence of DNA damage. All these cellular responses, and even the growth-inhibiting activity of YCL0426, can be readily reversed by Fe(II) repletion, indicating that iron sequestering is responsible, at least in part, for the antiproliferative activity of YCL0426. YCL0426 is a potent iron chelator that exerts significant antiproliferative activities by inducing G1/S arrest and DNA damage.

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Anticancer drugs and the regulation of Hedgehog genes GLI1 and PTCH1, a comparative study in nonmelanoma skin cancer cell lines

imageNonmelanoma skin cancer is the most common cancer in humans, comprising mainly basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC proliferation is highly dependent on the Hedgehog signaling pathway. We aimed to investigate a panel of anticancer drugs with known activity against skin cancer for their therapeutic potential in localized, enhanced topical treatment of SCC and BCC. Cytotoxicity profiles for vismodegib, 5-fluorouracil (5-FU), methotrexate (MTX), cisplatin, bleomycin, and vorinostat were established in terms of half maximal inhibitory concentration values in a panel of immortalized keratinocytes (HaCaT), BCC (UWBCC1 and BCC77015), and SCC (A431 and SCC25) cell lines. The impact of treatment on the regulation of Hedgehog pathway target genes (GLI1 and PTCH1), measured by real-time PCR, was compared between UWBCC1 and HaCaT. Varying cell line sensitivity profiles to the examined anticancer drugs were observed. Generally, 24-h drug exposure was sufficient to reduce cell viability. We found that 5-FU, MTX, and cisplatin significantly downregulated the expression of two genes controlled by the Hedgehog pathway (≤25-, 2.9-, and 12.5-fold, respectively, for GLI1 in UWBCC1 cells at 48 h, P

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Gallic acid induces G1 phase arrest and apoptosis of triple-negative breast cancer cell MDA-MB-231 via p38 mitogen-activated protein kinase/p21/p27 axis

imageGallic acid (GA) possesses potential antitumoral activity on different types of malignancies. In this study, we aimed to explore the antitumoral effects of GA on triple-negative breast cancer (TNBC) cells, the breast cancer cells showing resistance to hormonal therapy or HER2 receptor targeting therapy. We observed that GA treatment significantly decreased the cell viability of human TNBC cell line MDA-MB-231 and HS578T in a dose-dependent manner. In addition, GA exerted a relative lower cytotoxicity on noncancer breast fibroblast MCF-10F. Next, we analyzed the changes of cell-cycle distribution in response to GA treatment and found that GA led to an increase of G0/G1 and sub-G1 phase ratio in MDA-MB-231 cells. We further explored the crucial mediators controlling cell cycle and inducing apoptotic signaling, and the findings showed that GA downregulated cyclin D1/CDK4 and cyclin E/CDK2, upregulated p21Cip1and p27Kip1, and induced activation of caspase-9 and caspase-3. In addition, we demonstrated that p38 mitogen-activated protein kinase was involved in the GA-mediated cell-cycle arrest and apoptosis. Collectively, our findings indicate that GA inhibits the cell viability of TNBC cells, which may attribute to the G1 phase arrest and cellular apoptosis via p38 mitogen-activated protein kinase/p21/p27 axis. Thus, we suggest that GA could be beneficial to TNBC treatment.

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Rhabdomyosarcoma cells are susceptible to cell death by LDK378 alone or in combination with sorafenib independently of anaplastic lymphoma kinase status

imageAnaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is often overexpressed in rhabdomyosarcoma (RMS). However, its oncogenic and functional role in RMS remains unclear. Therefore, we investigated the antitumor activity of LDK378 (ceritinib), a new second-generation ALK inhibitor approved for patients with ALK-positive non-small-cell lung cancers. Here, we report that LDK378 reduces cell viability and induces cell death in RMS cell lines at low micromolar IC50 concentrations irrespective of ALK expression levels or phosphorylation status. Compared with Karpas 299 non-Hodgkin's lymphoma cells carrying the NPM–ALK fusion gene, RMS cell lines proved to be far less sensitive to LDK378. The broad-range caspase inhibitor zVAD.fmk significantly protects RMS cells from LDK378-mediated cell death, indicating that LDK378 induces caspase-dependent apoptotic cell death. Before the onset of apoptosis, LDK378 reduces phosphorylation of AKT, S6 ribosomal protein, STAT3 and – to a lesser extent – phosphorylation of ERK, showing that it suppresses key survival pathways. Importantly, we identify a synergistic induction of cell death by combining subtoxic concentrations of LDK378 with the multitargeting kinase inhibitor sorafenib. Calculation of the combination index confirmed that this interaction is synergistic. Also, LDK378 cooperates with sorafenib to significantly reduce colony formation of RMS cells, showing that this combination affects long-term clonogenic growth. In conclusion, LDK378 induces caspase-dependent apoptotic cell death in RMS cells independent of their ALK status and synergizes at subtoxic concentrations with sorafenib to induce cell death. These findings have important implications for the use of LDK378 in RMS.

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Early tumor shrinkage indicates a favorable response to bevacizumab-based first-line chemotherapy for metastatic colorectal cancer

imageA close correlation between early tumor shrinkage (ETS) and overall survival (OS) has been shown in antiepidermal growth factor receptor antibody-based chemotherapies for metastatic colorectal cancer (mCRC), but the clinical impact of ETS in bevacizumab-based chemotherapy has not been adequately clarified. Clinical data of mCRC patients who started initial chemotherapy without antiepidermal growth factor receptor antibody from 2005 to 2010 were retrospectively evaluated. The relative change in tumor size after 8 weeks of chemotherapy expected from the first image assessment [estimated ETS (EETS)] and the relative change in the tumor size at the nadir compared with the baseline [depth of response (DPR)] were examined. Seventy-three patients were enrolled and 61 patients were evaluable for survival by simple regression analysis. Bevacizumab-based chemotherapies were administered to 40 (66%) patients. The median EETS, DPR, progression-free survival, and OS were 16.1%, 27.2%, 8.0 months, and 19.5 months, respectively. Progression-free survival showed a positive correlation with OS (R2=0.429), whereas EETS and DPR were less correlated with OS (R2=0.0682, 0.186). EETS was well correlated with DPR (R2=0.659). Patients with EETS greater than 16.12% were predicted to achieve tumor shrinkage of more than 30% at the maximum response. EETS in bevacizumab-treated mCRC showed a close correlation with DPR, which suggested that EETS might be useful, indicating a favorable response in treatment with bevacizumab-based chemotherapy.

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Subtype-specific cancer-associated fibroblasts contribute to the pathogenesis of uterine leiomyoma.

Recent genomic studies have identified subtypes of uterine leiomyoma (LM) with distinctive genetic alterations. Here we report the elucidation of the biological characteristics of the two most prevalent LM subtypes, MED12 mutant (MED12-LM) and HMGA2-overexpressing (HMGA2-LM) LM. Since each tumor carries only one genetic alteration, both subtypes are considered to be monoclonal. Approximately 90% of cells in HMGA2-LM were smooth muscle cells (SMC) with HMGA2 overexpression. In contrast, MED12-LM consisted of similar numbers of SMC and non-SMC, which were mostly tumor-associated fibroblasts (TAF). Paradoxically, TAF carried no mutations in MED12, suggesting an interaction between SMC and TAF to coordinate their growth. The higher amount of ECM in MED12-LM than HMGA2-LM was partially due to the high concentration of collagen-producing TAF. SMC growth in a xenograft assay was driven by progesterone in both LM subtypes. In contrast, TAF in MED12-LM proliferated in response to estradiol, whereas progesterone had no effect. The high concentration of estrogen-responsive TAF in MED12-LM explains the inconsistent discoveries between in vivo and in vitro studies on the mitogenic effect of estrogen and raises questions regarding the accuracy of previous studies utilizing MED12-LM cell culture. In addition, the differential effects of estradiol and progesterone on these LM subtypes emphasize the importance of subtypes and genotypes in designing non-surgical therapeutic strategies for LM.

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RUNX1 upregulation by cytotoxic drugs promotes apoptosis

Mutations in the RUNX1 gene have been associated with chemotherapy resistance and poor prognosis in patients with acute myeloid leukemia (AML), T cell acute lymphoblastic leukemia (T-ALL) and myelodysplastic syndromes (MDS). However, the underlying mechanisms connecting RUNX1 to the success of therapy remain elusive. Here we explore the hypothesis that RUNX1 is directly involved in the response of hematopoietic cells to cytotoxic agents. RUNX1 was upregulated post-transcriptionally by cytotoxic agents in C57BL/6 mice in vivo and hematopoietic cell lines. Upregulation was also seen in primary human AML cells after treatment with cytarabine in vitro. Upon overexpression, RUNX1 restricted proliferation, promoted apoptosis, and augmented the DNA damage response. This unknown activity of RUNX1 required an intact runt homology domain (RHD), a domain where most leukemia-associated point mutations cluster. Consistent with this, two RHD-defective RUNX1 proteins lacked any anti-proliferative or apoptotic activity, and RHD-defective (K83N, N109D) mutant RUNX1 conferred resistance to ionizing radiation when overexpressed in Ba/F3 cells under certain conditions. Our experiments reveal a novel function of RUNX1 and offer an explanation for the link between RUNX1 mutations and chemotherapy and radiation resistance. Moreover, these data suggest that pharmacological modulation of RUNX1 might be an attractive new approach to treat hematological malignancies.

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New generation nanomedicines constructed from self-assembling small molecule prodrugs alleviate cancer drug toxicity

The therapeutic index for chemotherapeutic drugs is determined in part by systemic toxicity, so strategies for dose intensification to improve efficacy must also address tolerability. In addressing this issue, we have investigated a novel combinatorial strategy of reconstructing a drug molecule and using sequential drug-induced nanoassembly to fabricate supramolecular nanomedicines (SNM). Using cabazitaxel (CTX) as a target agent, we established that individual synthetic prodrugs tethered with polyunsaturated fatty acids were capable of recapitulating self-assembly behavior independent of exogenous excipients. The resulting SNM could be further refined by PEGylation with amphiphilic copolymers suitable for preclinical studies. Among these CTX derivatives, docosahexaenoic acid-derived compound 1 retained high anti-proliferative activity. SNM assembled with compound 1 displayed an unexpected enhancement of tolerability in animals along with effective therapeutic efficacy in a mouse xenograft model of human cancer, compared to free drug administered in its clinical formulation. Overall, our studies showed how attaching flexible lipid chains to a hydrophobic and highly toxic anticancer drug can convert it to a systemic self-deliverable nanotherapy, preserving its pharmacological efficacy while improving its safety profile.

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SGK1 is a critical component of an AKT-independent pathway essential for PI3K-mediated tumor development and maintenance

Activation of the PI3K-AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, while necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases. In particular, SGK1 was found to be essential for proliferation and survival of thyroid cancer cells harboring PI3K-activating mutations. Notably, co-targeting SGK1 and AKT resulted in significantly higher growth suppression than inhibiting either PI3K or AKT alone. Overall, these findings underscore the clinical relevance of AKT-independent pathways in tumors driven by genetic lesions targeting the PI3K cascade.

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A synthetic CD8{alpha}:MyD88 co-receptor enhances CD8+ T cell responses to weakly immunogenic and lowly expressed tumor antigens

T cell-based immunotherapies are a promising approach for patients with advanced cancers. However, various obstacles limit T cell efficacy, including suboptimal T cell receptor (TCR) activation and an immunosuppressive tumor environment. Here we developed a fusion protein by linking CD8α and MyD88 (CD8α:MyD88) to enhance CD8+ T cell responses to weakly immunogenic and poorly expressed tumor antigens. CD8α:MyD88-engineered T cells exhibited increased proliferation and expression of effector and co-stimulatory molecules in a tumor antigen-dependent manner. These effects were accompanied by elevated activation of TCR and Toll-like receptor (TLR) signaling-related proteins. CD8α:MyD88-expressing T cells improved anti-tumor responses in mice. Enhanced anti-tumor activity was associated with a unique tumor cytokine/chemokine signature, improved T cell infiltration, reduced markers of T cell exhaustion, elevated levels of proteins associated with antigen presentation, and fewer macrophages with an immunosuppressive phenotype in tumors. Given these observations, CD8α:MyD88 represents a unique and versatile approach to help overcome immunosuppression and enhance T cell responses to tumor antigens.

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Protein acyltransferase DHHC3 regulates breast tumor growth, oxidative stress and senescence

DHHC-type protein acyltransferases may regulate the localization, stability and/or activity of their substrates. In this study, we show that the protein palmitoyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer. Elevated expression of DHHC3 correlated with diminished patient survival in breast cancer and six other human cancer types. ZDHHC3 ablation in human MDA-MB-231 mammary tumor cell xenografts reduced the sizes of both the primary tumor and metastatic lung colonies. Gene array data and fluorescence dye assays documented increased oxidative stress and senescence in ZDHHC3-ablated cells. ZDHHC3-ablated tumors also showed enhanced recruitment of innate immune cells (anti-tumor macrophages, natural killer cells) associated with clearance of senescent tumors. These anti-tumor effects were reversed upon reconstitution with wildtype, but not enzyme-active site-deficient DHHC3. Concomitant ablation of the upregulated oxidative stress protein TXNIP substantially negated the effects of ZDHHC3 depletion on oxidative stress and senescence. Diminished DHHC3-dependent palmitoylation of ERGIC3 protein likely played a key role in TXNIP upregulation. In conclusion, DHHC3-mediated protein palmitoylation supports breast tumor growth by modulating cellular oxidative stress and senescence.

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Small molecule inhibition of PD-1 transcription is an effective alternative to antibody blockade in cancer therapy

The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase GSK-3α/β, is a central regulator of PD-1 transcription in CD8+ T cells. Here, we show that the use of small molecule inhibitors of GSK-3α/β (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti-PD-1 and PDL-1 blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings. Further, the conditional genetic deletion of GSK-3α/β reduced PD-1 expression on CD8+ T cells, and limited B16 pulmonary metastasis to the same degree as PD-1 gene deficiency. In each model, GSK-3i inhibited PD-1 expression on tumor infiltrating lymphocytes (TILs), while increasing Tbx21 (T-bet) transcription, and the expression of CD107a+ (LAMP1) and granzyme B (GZMB) on CD8+ T-cells. Lastly, the adoptive transfer of T-cells treated ex vivo with a GSK-3 inhibitor delayed the onset of EL4 lymphoma growth to a similar extent as anti-PD-1 pre-treatment. Overall, our findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8+ T-cell function in cancer therapy to a similar degree as PD-1 blocking antibodies.

http://ift.tt/2zFtL0j

BTSA1 Activates BAX to Promote Apoptosis in Acute Myeloid Leukemia [Research Watch]

The small-molecule BAX activator BTSA1 promotes apoptosis of AML cells in vitro and in vivo.



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Nivolumab Induces Tumor Evolution in Patients with Melanoma [Research Watch]

Nivolumab treatment results in immunoediting and loss of tumor cells expressing neoantigens.



http://ift.tt/2yw4RSZ

SEMA3C Depletion Promotes Neuroblastoma Metastatic Dissemination [Research Watch]

A neuroblastoma chick embryo xenograft model recapitulates tumor initiation and dissemination.



http://ift.tt/2gycLEu

Breast Cancer Cells Recycle Ammonia to Generate Amino Acids [Research Watch]

Ammonia generated from glutamate metabolism enhances the proliferation of breast cancer cells.



http://ift.tt/2yw4h7L

Suppression of adaptive responses to targeted cancer therapy by transcriptional repression [Research Briefs]

Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adaptive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant, which THZ1 can exploit by blocking dynamic transcriptional responses, remodeling of enhancers and key signalling outputs required for tumor cell survival in the setting of targeted therapy. These findings suggest that the addition of THZ1 to targeted therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations.



http://ift.tt/2gzohPZ

Substance P and dopamine interact to modulate the distribution of delta-opioid receptors on cholinergic interneurons in the striatum

Abstract

It recently been demonstrated that predictive learning induces a persistent accumulation of delta-opioid receptors (DOPr's) at the somatic membrane of cholinergic interneurons (CINs) in the nucleus accumbens shell (Nac-S). This accumulation is required for predictive learning to influence subsequent choice between goal-directed actions. The current experiments investigated the local neurochemical events responsible for this translocation. We found that (1) local administration of substance P into multiple striatal sub-territories induced DOPr translocation and (2) that this effect was mediated by the NK1 receptor, likely through its expression on CINs. Interestingly, whereas intrastriatal infusion of the D1 agonist chloro-APB reduced the DOPr translocation on CINs and infusion of the D2 agonist quinpirole had no effect, co-administration of both agonists again generated DOPr translocation, suggesting the effect of the D1 agonist alone was due to receptor internalization. In support of this, local administration of cocaine was found to increase DOPr translocation as was chloro-APB when co-administered with the DOPr antagonist naltrindole. These studies provide the first evidence of delta-opioid receptor translocation in striatal cholinergic interneurons outside of the accumbens shell, and suggest that, despite differences in local striatal neurochemical microenvironments, a similar molecular mechanism – involving an interaction between dopamine and SP signalling via NK1R – regulates DOPr translocation in multiple striatal regions. To our knowledge, this represents a novel mechanism by which DOPr distribution is regulated, that may be particularly relevant to learning-induced DOPr trafficking.

This article is protected by copyright. All rights reserved.



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The Neural Oscillations of Speech Processing and Language Comprehension: State of the Art and Emerging Mechanisms

Abstract

Neural oscillations subserve a broad range of functions in speech processing and language comprehension. On the one hand, speech contains—somewhat—repetitive trains of air pressure bursts that occur at three dominant amplitude modulation frequencies, physically marking the linguistically meaningful progressions of phonemes, syllables, and intonational phrase boundaries. To these acoustic events, neural oscillations of isomorphous operating frequencies are thought to synchronize, presumably resulting in an implicit temporal alignment of periods of neural excitability to linguistically meaningful spectral information on the three low-level linguistic description levels. On the other hand, speech is a carrier signal that codes for high-level linguistic meaning, such as syntactic structure and semantic information—which cannot be read from stimulus acoustics, but must be acquired during language acquisition and decoded for language comprehension. Neural oscillations subserve the processing of both syntactic structure and semantic information. Here, I synthesize a mapping from each linguistic processing domain to a unique set of subserving oscillatory mechanisms—the mapping is plausible given the role ascribed to different oscillatory mechanisms in different sub-functions of cortical information processing and faithful to the underlying electrophysiology. In sum, the present article provides an accessible and extensive review of the functional mechanisms that neural oscillations subserve in processing and language comprehension.

This article is protected by copyright. All rights reserved.



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Deep Brain stimulation of the Nucleus Basalis of Meynert attenuates early EEG components associated with defective sensory gating in patients with Alzheimer disease – a two-case study

Abstract

Alzheimer′s disease (AD) is associated with deterioration of memory and cognitive function and a degeneration of neurons of the nucleus basalis of Meynert (NBM). The NBM is the major input source of Acetylcholine (ACh) to the cortex. The decreasing cholinergic innervation of the cortex due to degeneration of the NBM might be the cause of loss of memory function. NBM-Deep Brain Stimulation (NBM-DBS) is considered to serve as a potential therapeutic option for AD patients by supporting residual cholinergic transmission to stabilize oscillatory activity in memory relevant circuits. However, whether DBS could improve sensory memory functions in AD patients is not clear. Here, in a passive auditory oddball paradigm AD patients (N = 2) listened to repetitive background tones (standard tones) randomly interrupted by frequency deviants in two blocks with NBM-DBS OFF and then NBM-DBS ON, while age-matched healthy controls (N=6) repeated the experiment twice. The Mismatch Negativity in NBM-DBS OFF significantly differed from controls in both blocks, but not under NBM-DBS, which was likely due to a pronounced P50 increase overlapping with the N1 in NBM-DBS OFF. This early complex of EEG components recovered under stimulation to a normal level as defined by responses in controls. In this temporal interval we found in patients with NBM-DBS ON (but not with NBM-DBS OFF) and in controls a strong repetition suppression effect to standard tones – with more attenuated responses to frequently repeated standard tones. This highlights the role of NBM-DBS for sensory gating of familiar auditory information into sensory memory.

This article is protected by copyright. All rights reserved.



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Surveying the Literature: Synopsis of Recent Key Publications

No abstract available

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Effect of Stellate Ganglion Block on the Regional Hemodynamics of the Upper Extremity: A Randomized Controlled Trial

BACKGROUND: BACKGROUND:The success of stellate ganglion block (SGB) is traditionally determined on the basis of findings such as Horner's syndrome, temperature rise in the face, hyperemia of the tympanic membrane, and nasal congestion. However, decreases in vascular resistance and increases in blood flow in the arm may be more meaningful findings. To date, the effect of SGB on the regional hemodynamics of the arm has not been evaluated using pulsed-wave Doppler ultrasound. METHODS: METHODS:A total of 52 patients who were to undergo orthopedic surgery of the forearm were randomly assigned to either the mepivacaine group (SGB with 5 mL of 0.5% mepivacaine) or the saline group (SGB with 5 mL of normal saline). Before surgery, a single anesthesiologist performed a SGB under ultrasound guidance. The temperature of the upper extremity and the resistance index and blood flow in the brachial artery were measured before SGB, 15 and 30 minutes after SGB, and 1 hour after surgery. The severity of pain, requirement for rescue analgesics, and side effects of the local anesthetic agent were all documented. RESULTS: RESULTS:After SGB, the resistance index decreased significantly and the blood flow increased significantly in the brachial artery of members of the mepivacaine group (15 minutes: P = .004 and P

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Postoperative Outcomes in Obstructive Sleep Apnea Patients Undergoing Cardiac Surgery: A Systematic Review and Meta-Analysis of Comparative Studies

BACKGROUND: BACKGROUND:Obstructive sleep apnea (OSA) is a common comorbidity in patients undergoing cardiac surgery and may predispose patients to postoperative complications. The purpose of this meta-analysis is to determine the evidence of postoperative complications associated with OSA patients undergoing cardiac surgery. METHODS: METHODS:A literature search of Cochrane Database of Systematic Reviews, Medline, Medline In-process, Web of Science, Scopus, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL until October 2016 was performed. The search was constrained to studies in adult cardiac surgical patients with diagnosed or suspected OSA. All included studies must report at least 1 postoperative complication. The primary outcome is major adverse cardiac or cerebrovascular events (MACCEs) up to 30 days after surgery, which includes death from all-cause mortality, myocardial infarction, myocardial injury, nonfatal cardiac arrest, revascularization process, pulmonary embolism, deep venous thrombosis, newly documented postoperative atrial fibrillation (POAF), stroke, and congestive heart failure. Secondary outcome is newly documented POAF. The other exploratory outcomes include the following: (1) postoperative tracheal intubation and mechanical ventilation; (2) infection and/or sepsis; (3) unplanned intensive care unit (ICU) admission; and (4) duration of stay in hospital and ICU. Meta-analysis and meta-regression were conducted using Cochrane Review Manager 5.3 (Cochrane, London, UK) and OpenBUGS v3.0, respectively. RESULTS: RESULTS:Eleven comparative studies were included (n = 1801 patients; OSA versus non-OSA: 688 vs 1113, respectively). MACCEs were 33.3% higher odds in OSA versus non-OSA patients (OSA versus non-OSA: 31% vs 10.6%; odds ratio [OR], 2.4; 95% confidence interval [CI], 1.38–4.2; P = .002). The odds of newly documented POAF (OSA versus non-OSA: 31% vs 21%; OR, 1.94; 95% CI, 1.13–3.33; P = .02) was higher in OSA compared to non-OSA. Even though the postoperative tracheal intubation and mechanical ventilation (OSA versus non-OSA: 13% vs 5.4%; OR, 2.67; 95% CI, 1.03–6.89; P = .04) were significantly higher in OSA patients, the length of ICU stay and hospital stay were not significantly prolonged in patients with OSA compared to non-OSA. The majority of OSA patients were not treated with continuous positive airway pressure therapy. Meta-regression and sensitivity analysis of the subgroups did not impact the OR of postoperative complications for OSA versus non-OSA groups. CONCLUSIONS: CONCLUSIONS:Our meta-analysis demonstrates that after cardiac surgery, MACCEs and newly documented POAF were 33.3% and 18.1% higher odds in OSA versus non-OSA patients, respectively. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Accepted for publication August 16, 2017. Funding: The STOP-Bang tool is proprietary to University Health Network. This study is supported by University Health Network Foundation, and Department of Anesthesiology, University Health Network, University of Toronto. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Frances Chung, MD, FRCPC, Department of Anesthesiology and Pain Medicine, Toronto Western Hospital, University Health Network, 399 Bathurst St, Toronto, Ontario, M5T 2S8, Canada. Address e-mail to frances.chung@uhn.ca. © 2017 International Anesthesia Research Society

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Physiology and Role of Intraocular Pressure in Contemporary Anesthesia

More than 26 million Americans suffer with cataracts, and with 3.6 million cataract extractions performed annually in the United States, it is the most common surgical procedure. The integrity of the delicate structures of the eye that mediate vision is dependent on the intraocular pressure (IOP). Yet, IOP acts to compress the vessels within the globe—akin to a Starling resistor—and is a key component that determines the ocular perfusion pressure, defined as the difference between arterial pressure and IOP. The retina is one of the most metabolically active tissues in the body, and its functional integrity is dependent on an adequate blood supply, with retinal function linearly related to the ocular perfusion pressure. Retinal cell death has been demonstrated at low perfusion pressures (below 50 mm Hg). Modern ophthalmic surgery involves globe irrigation, manipulation, and instrumentation, resulting in dynamic pressure fluxes within the eye. Marked elevations of IOP (up to 4–5 times the normal value) with consequent borderline retinal and optic disk perfusion pressures occur for prolonged periods during many ophthalmic procedures. General surgeries, including laparoscopic, spinal, and cardiac procedures, especially, with their demand for steep Trendelenburg or prolonged prone positioning and/or hypotensive anesthesia, can induce IOP changes and ocular perfusion imbalance. These rapid fluctuations in IOP, and so in perfusion, play a role in the pathogenesis of the visual field defects and associated ocular morbidity that frequently complicate otherwise uneventful surgeries. The exact etiology of such outcomes is multifactorial, but ocular hypoperfusion plays a significant and frequently avoidable role. Those with preexisting compromised ocular blood flow are especially vulnerable to intraoperative ischemia, including those with hypertension, diabetes, atherosclerosis, or glaucoma. However, overly aggressive management of arterial pressure and IOP may not be possible given a patient's comorbidity status, and it potentially exposes the patient to risk of catastrophic choroidal hemorrhage. Anesthetic management significantly influences the pressure changes in the eye throughout the perioperative period. Strategies to safeguard retinal perfusion, reduce the ischemic risk, and minimize the potential for expulsive bleeding must be central to the anesthetic techniques selected. This review outlines: important physiological principles; ophthalmic and general procedures most likely to develop damaging IOP levels and their causative factors; the effect of anesthetic agents and techniques on IOP; recent scientific evidence highlighting the significance of perfusion changes during surgery; and key aspects of postoperative visual loss and management approaches for high-risk patients presenting for surgery. Accepted for publication September 6, 2017. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Dermot J. Kelly, MRCPI, FFARCSI, DABA, Department of Anesthesia, Royal Victoria Eye and Ear Hospital, Adelaide Rd, Dublin 2, Ireland. Address e-mail to drdermotkelly@gmail.com. © 2017 International Anesthesia Research Society

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Insight Into Our Technology: Anesthesia Information Management Systems

Anesthesia information management systems (AIMS) have evolved from simple, automated intraoperative record keepers in a select few institutions to widely adopted, sophisticated hardware and software solutions that are integrated into a hospital's electronic health record system and used to manage and document a patient's entire perioperative experience. AIMS implementations have resulted in numerous billing, research, and clinical benefits, yet there remain challenges and areas of potential improvement to AIMS utilization. This article provides an overview of the history of AIMS, the components and features of AIMS, and the benefits and challenges associated with implementing and using AIMS. As AIMS continue to proliferate and data are increasingly shared across multi-institutional collaborations, visual analytics and advanced analytics techniques such as machine learning may be applied to AIMS data to reap even more benefits. Accepted for publication September 8, 2017. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Allan F. Simpao, MD, MBI, Department of Anesthesiology and Critical Care, Division of General Anesthesia, Perelman School of Medicine at the University of Pennsylvania and The Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104. Address e-mail to simpaoa@email.chop.edu. © 2017 International Anesthesia Research Society

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Fatigue Risk Management: The Impact of Anesthesiology Residents’ Work Schedules on Job Performance and a Review of Potential Countermeasures

Long duty periods and overnight call shifts impair physicians' performance on measures of vigilance, psychomotor functioning, alertness, and mood. Anesthesiology residents typically work between 64 and 70 hours per week and are often required to work 24 hours or overnight shifts, sometimes taking call every third night. Mitigating the effects of sleep loss, circadian misalignment, and sleep inertia requires an understanding of the relationship among work schedules, fatigue, and job performance. This article reviews the current Accreditation Council for Graduate Medical Education guidelines for resident duty hours, examines how anesthesiologists' work schedules can affect job performance, and discusses the ramifications of overnight and prolonged duty hours on patient safety and resident well-being. We then propose countermeasures that have been implemented to mitigate the effects of fatigue and describe how training programs or practice groups who must work overnight can adapt these strategies for use in a hospital setting. Countermeasures include the use of scheduling interventions, strategic naps, microbreaks, caffeine use during overnight and extended shifts, and the use of bright lights in the clinical setting when possible or personal blue light devices when the room lights must be turned off. Although this review focuses primarily on anesthesiology residents in training, many of the mitigation strategies described here can be used effectively by physicians in practice. Accepted for publication September 8, 2017. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Keith J. Ruskin, MD, Department of Anesthesia and Critical Care, University of Chicago, 5841 S Maryland Ave, MC4028, Chicago, IL 60637. Address e-mail to ruskin@uchicago.edu. © 2017 International Anesthesia Research Society

http://ift.tt/2gy6F74

Noninfectious Fever in the Near-Term Pregnant Rat Induces Fetal Brain Inflammation: A Model for the Consequences of Epidural-Associated Maternal Fever

BACKGROUND: BACKGROUND:Women laboring with epidural analgesia experience fever much more frequently than do women who chose other forms of analgesia, and maternal intrapartum fever is associated with numerous adverse consequences, including brain injury in the fetus. We developed a model of noninfectious inflammatory fever in the near-term pregnant rat to simulate the pathophysiology of epidural-associated fever and hypothesized that it would produce fetal brain inflammation. METHODS: METHODS:Twenty-four pregnant Sprague-Dawley rats were studied at 20 days gestation (term: 22 days). Dams were treated by injection of rat recombinant interleukin (IL)-6 or vehicle at 90-minute intervals, and temperature was monitored every 30 minutes. Eight hours after the first treatment, dams were delivered of fetuses and then killed. Maternal IL-6 was measured at delivery. Fetal brains (n = 24) were processed and stained for ED-1/CD68, a marker for activated microglia, and cell counts in the lateral septal and hippocampal brain regions were measured. Fetal brains were also stained for cyclooxygenase-2 (COX-2), a downstream marker of neuroinflammation. Eight fetal brains were further analyzed for quantitative forebrain COX-2 by Western blotting compared to a β-actin standard. Maternal temperature and IL-6 levels were compared between treatments, as were cell counts, COX-2 staining, and COX-2 levels by Mann-Whitney U test, repeated-measures analysis of variance, or Fisher exact test, as appropriate. RESULTS: RESULTS:Injection of rat IL-6 at 90-minute intervals produced an elevation of maternal temperature compared to vehicle (P

http://ift.tt/2yvR6nj

Oesophageal motor function in chronic intestinal idiopathic pseudo-obstruction: a study with high-resolution manometry

Chronic intestinal idiopathic pseudo-obstruction (idiopathic CIPO) is a rare heterogeneous condition for which the different phenotypes are difficult to be established. Oesophageal motility has shown to be impaired in patients with idiopathic CIPO at traditional manometry, whereas no studies have assessed it by high resolution manometry (HRM).

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The spectrum of Charcot-Marie-Tooth disease due to myelin protein zero: An electrodiagnostic, nerve ultrasound and histological study

Charcot-Marie-Tooth disease (CMT) is the most frequent inherited neuromuscular disorder and encompasses heterogeneous motor-sensory length-dependent polyneuropathies. CMT manifests commonly in the first-second decade with moderate functional involvement and slow evolution. Variations in age of onset, from early infancy to late adulthood, and degree of severity, from an asymptomatic neuropathy to loss of the ambulatory autonomy, are not necessarily linked to specific genotypes. Clinical phenotypes, mode of inheritance and nerve conduction study (NCS) still address genetic tests in the Next-Generation Sequencing era (Rossor et al., 2016).

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Motor cortex excitability in seizure-free STX1B mutation carriers with a history of epilepsy and febrile seizures

Febrile seizures affect 2-4% of all children and have been related to strong genetic predisposition (Berg et al., 2013). Recently, mutations of the STX1B gene have been identified as a shared genetic mechanism implicated in the pathogenesis of febrile seizures with or without epilepsy (Schubert et al., 2014). STX1B encodes the presynaptic protein syntaxin-1B, a significant component of the soluble-N-ethylmaleimide sensitive factor attachment receptor (SNARE) complex, which tethers synaptic vesicles in the presynaptic membrane and mediates the vesicle exocytosis and release of neurotransmitters at the synapse (Kearney, 2015).

http://ift.tt/2grQAMe

Dexmedetomidine promotes biomimetic non-rapid eye movement stage 3 sleep in humans: A pilot study

Sleep is a natural occurring state of decreased arousal that is crucial for normal cardiovascular, immune and cognitive function (Rosenberg-Adamsen et al., 1996; Saper et al., 2010). However, the principal sedative drugs, most of which modulate the γ amino butyric acid A (GABAA) receptor, do not produce the neurophysiological oscillations of sleep (Akeju et al., 2017). Rather, they produce neurophysiological oscillations that reflect cortical circuit disruptions, which manifest as electroencephalogram frontal beta oscillations, frontal alpha oscillations, burst suppression and isoelectricity (Patat et al., 1994; Feinberg et al., 2000; van Lier et al., 2004; Purdon et al., 2013; Akeju et al., 2014a; Akeju et al., 2014b, Akeju et al., 2017).

http://ift.tt/2zqhiMU

Cerebellar transcranial direct current stimulation improves adaptive postural control

Adaptive postural control is essential for almost all aspects of every day life. Impaired postural control results in substantial functional limitations in advanced age (Maki and McIlroy, 1996) and in pathological ageing conditions like stroke (Beyaert et al., 2015), Parkinson's disease (Schoneburg et al., 2013) or multiple sclerosis (Huisinga et al., 2012). Although rehabilitation and conditioning programs have shown promising results in recovery of postural control, those interventions are typically time and cost intensive and may only yield moderate effects (Howard-Wilsher et al., 2016; Smania et al., 2011; Yitayeh and Teshome, 2016).

http://ift.tt/2gqHQWO

Early corticospinal tract damage in prodromal SCA2 revealed by EEG-EMG and EMG-EMG coherence

SCA2 is caused by a polyglutamine-coding CAG trinucleotide repeat expansion (>34) in the ataxin-2 gene (Pulst et al., 1996). The complex SCA2 phenotype results from multi-system degeneration, involving cerebellum, spinal cord, brainstem and thalamus (Rüb et al., 2013). The prodromal stage of SCA2 was defined here according to Maas et al. (2015) as individuals with already detectable central and/or peripheral nervous system changes but without or with only minimal signs of ataxia (Maas et al., 2015).

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Cervical vestibular evoked myogenic potential tuning properties of patients with recurrent peripheral vestibulopathy: Is it Meniere’s disease without hearing loss?

Clinicians often encounter patients who complain of episodic vertigo. Meniere's disease (MD) and vestibular migraine (VM) are representative diseases in this category. Recently, new diagnostic criteria for both of these diseases have been published (Lopez-Escamez et al., 2015; Lempert et al., 2012). MD patients exhibit auditory symptoms in association with episodic vertigo attacks, while VM patients also have migrainous symptoms in addition to these symptoms. However, many patients have episodic vertigo without auditory or migrainous symptoms.

http://ift.tt/2gpiN6C

Imaging Amyloid Tissues Stained with Luminescent Conjugated Oligothiophenes by Hyperspectral Confocal Microscopy and Fluorescence Lifetime Imaging

Amyloid deposition is a hallmark of different diseases and afflicts many different organs. This paper describes the application of luminescent conjugated oligothiophene fluorescence staining in combination with fluorescence microscopy techniques. This staining method represents a powerful tool for detection and exploration of protein aggregates in both clinical and scientific setups.

http://ift.tt/2gVtONz

EMS agency proposes ambulance chase car

The chase car would be available during a mass casualty event anywhere in the county; it could be provided to make up a BLS crew if all other avenues were exhausted

http://ift.tt/2yvZbbr

Application of MultiColor FlpOut Technique to Study High Resolution Single Cell Morphologies and Cell Interactions of Glia in Drosophila

Cells display different morphologies and establish a variety of interactions with their neighbors. This protocol describes how to reveal the morphology of single cells and to investigate cell-cell interaction by using the well-established Gal4/UAS expression system.

http://ift.tt/2iqKoZf

Nivolumab Receives Accelerated Approval from FDA for Advanced Liver Cancer

The FDA has granted accelerated approval to the immunotherapy drug nivolumab (Opdivo®) for patients with advanced liver cancer who have previously been treated with the targeted therapy sorafenib (Nexavar®).



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Longitudinal study of Staphylococcus aureus colonization and infection in a cohort of swine veterinarians in the United States

People working with pigs are at elevated risk of harboring methicillin resistant S. aureus (MRSA) in their nose, which is attributable to occupational exposure to animals harboring livestock adapted S. aureus. To...

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What EMS leaders, educators can learn from continuing education data

An analysis of 8.7 million CAPCE continuing education records show how and when paramedics and EMTs earn CE for state and National Registry recertification

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An Ultrasonic Tool for Nerve Conduction Block in Diabetic Rat Models

This work presents the methodology of applying high intensity-focused ultrasound to block the action potentials of diabetic neuropathic nerves.

http://ift.tt/2zG0dzw

Quantitative Rapid Assessment of Leukoaraiosis in CT

Abstract

Purpose

The severity of white matter lesions (WML) is a risk factor of hemorrhage and predictor of clinical outcome after ischemic stroke; however, in contrast to magnetic resonance imaging (MRI) reliable quantification for this surrogate marker is limited for computed tomography (CT), the leading stroke imaging technique. We aimed to present and evaluate a CT-based automated rater-independent method for quantification of microangiopathic white matter changes.

Methods

Patients with suspected minor stroke (National Institutes of Health Stroke scale, NIHSS < 4) were screened for the analysis of non-contrast computerized tomography (NCCT) at admission and compared to follow-up MRI. The MRI-based WML volume and visual Fazekas scores were assessed as the gold standard reference. We employed a recently published probabilistic brain segmentation algorithm for CT images to determine the tissue-specific density of WM space. All voxel-wise densities were quantified in WM space and weighted according to partial probabilistic WM content. The resulting mean weighted density of WM space in NCCT, the surrogate of WML, was correlated with reference to MRI-based WML parameters.

Results

The process of CT-based tissue-specific segmentation was reliable in 79 cases with varying severity of microangiopathy. Voxel-wise weighted density within WM spaces showed a noticeable correlation (r = −0.65) with MRI-based WML volume. Particularly in patients with moderate or severe lesion load according to the visual Fazekas score the algorithm provided reliable prediction of MRI-based WML volume.

Conclusion

Automated observer-independent quantification of voxel-wise WM density in CT significantly correlates with microangiopathic WM disease in gold standard MRI. This rapid surrogate of white matter lesion load in CT may support objective WML assessment and therapeutic decision-making during acute stroke triage.



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Update on squamous cell carcinoma of the head and neck

Summary

At the annual ASCO meeting clinically relevant data concerning the management of advanced head and neck cancer that will influence clinical practice in the future were presented.

Chemoradiation with high-dose cisplatin remains the mainstay of treatment for patients with locally advanced squamous cell head and neck cancer. Adjuvant therapy with afatinib following chemoradiation failed to show clinical benefit. The combination of bevacizumab with platinum-based chemotherapy improved progression-free survival but did not lead to a significant difference in overall survival compared to chemotherapy alone. However, the addition of immunotherapy may improve multimodal treatment concepts in locally advanced disease and new treatment combinations might overcome resistance to checkpoint inhibition.



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Cancer-Testis Antigens as New Candidate Diagnostic Biomarkers for Transitional Cell Carcinoma of Bladder

Abstract

To evaluate the diagnostic potential of 23 candidate genes, belonging to a category of tumor-specific antigens known as cancer-testis antigens (CTAs), in transitional cell carcinoma (TCC) patients. The expression of 16 known candidate CTAs and seven testis restricted/selective genes, predominantly expressed in the testis, was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR). Urinary exfoliated cells (UECs) and cancerous tissues of 73 TCC patients were used as cases, while 25 tumor-free adjacent bladder tissue specimens along with bladder tissue specimens and UECs of five non-TCC individuals were analyzed as controls. Among the known CTAs only MAGEA3, MAGEB4, TSGA10, PIWIL2, OIP5, and ODF4 were expressed specifically in TCC tissues and UEC samples. ACTL7A, AURKC, and CGB2 were testis-restricted/selective genes that indicated specific expression in cases in comparison to controls. MAGEA3, MAGEB4, and ODF4 mRNA was detectable in more than 50% of both TCC tissues, and UEC samples. Slight differences were detected in the mRNA expression pattern of candidate genes between the UEC samples and tumor tissues. Different panels formed by combinations of these genes can show up to 95.9% and 94.5% of positivity in TCC tissues and UEC samples, respectively, suggesting their diagnostic and surveillance potential. Meanwhile the RT-PCR assay of at least MAGEA3, MAGEB4, and ODF4 may be particularly useful for diagnostic and surveillance of TCC in the form of a multi-biomarker panel.



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Comprehensive Endovascular and Open Surgical Management of Cerebral Arteriovenous Malformations

Surgery is the gold standard for accessible arteriovenious malformations (AVMs), and pre-operative embolization can simplify this procedure. We describe our approach for staged endovascular embolization and open resection of AVMs, and provide a representative clinical example highlighting the advantages of a comprehensively trained neurovascular surgeon leading a multi-disciplinary clinical team.

http://ift.tt/2yC62xG

Homeostatic plasticity in human extrastriate cortex following a simulated peripheral scotoma

Abstract

Neuroimaging and patient work over the past decade have indicated that, following retinal deafferentation, the human visual cortex undergoes a large-scale and enduring reorganization of its topography such that the classical retinotopic organization of deafferented visual cortex remaps to represent non-classical regions of visual space. Such long-term visual reorganization is proposed to occur through changes in the functional balance of deafferented visual circuits that engage more lasting changes through activity-dependent neuroplasticity. Here, we investigated the short-term changes in functional balance (short-term plasticity; homeostatic plasticity) that occur within deafferented human visual cortices. We recorded electroencephalogram (EEG) while observers were conditioned for 6 s with a simulated retinal scotoma (artificial scotoma) positioned 8.0° in the periphery. Visual evoked potentials (VEPs) evoked by the onset of sinusoidal visual probes that varied in their tilt were used to examine changes in cortical excitability within and around cortical representations of the simulated scotoma. Psychophysical orientation functions obtained from discrimination of visual probe tilt were used to examine alterations in the stimulus selectivity within the scotoma representations. Consistent with a mechanism of homeostatic disinhibition, an early extrastriate component of the VEP (the early phase P1) exhibited increased amplitude following the condition with a simulated scotoma relative to a stimulus-matched control condition. This increased visual cortical response was associated with a reduction in the slope of the psychophysical orientation function, suggesting a broader tuning of neural populations within scotoma representations. Together, these findings support a mechanism of disinhibition in promoting visual plasticity and topographical reorganization.



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Relative vibrotactile spatial acuity of the torso

Abstract

While tactile acuity for pressure has been extensively investigated, far less is known about acuity for vibrotactile stimulation. Vibrotactile acuity is important however, as such stimulation is used in many applications, including sensory substitution devices. We tested discrimination of vibrotactile stimulation from eccentric rotating mass motors with in-plane vibration. In 3 experiments, we tested gradually decreasing center-to-center (c/c) distances from 30 mm (experiment 1) to 13 mm (experiment 3). Observers judged whether a second vibrating stimulator ('tactor') was to the left or right or in the same place as a first one that came on 250 ms before the onset of the second (with a 50-ms inter-stimulus interval). The results show that while accuracy tends to decrease the closer the tactors are, discrimination accuracy is still well above chance for the smallest distance, which places the threshold for vibrotactile stimulation well below 13 mm, which is lower than recent estimates. The results cast new light on vibrotactile sensitivity and can furthermore be of use in the design of devices that convey information through vibrotactile stimulation.



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Planar covariance of upper and lower limb elevation angles during hand–foot crawling in healthy young adults

Abstract

Habitual quadrupeds have been shown to display a planar covariance of segment elevation angle waveforms in the fore and hind limbs during many forms of locomotion. The purpose of the current study was to determine if humans generate similar patterns in the upper and lower limbs during hand–foot crawling. Nine healthy young adults performed hand–foot crawling on a treadmill at speeds of 1, 2, and 3 km/h. A principal component analysis (PCA) was applied to the segment elevation angle waveforms for the upper (upper arm, lower arm, and hand) and lower (thigh, shank, and foot) limbs separately. The planarity of the elevation angle waveforms was determined using the sum of the variance explained by the first two PCs and the orientation of the covariance plane was quantified using the direction cosines of the eigenvector orthogonal to the plane, projected upon each of the segmental semi-axes. Results showed that planarity of segment elevation angles was maintained in the upper and lower limbs (explained variance >97%), although a slight decrease was present in the upper limb when crawling at 3 km/h. The orientation of the covariance plane was highly limb-specific, consistent with animal studies and possibly related to the functional neural control differences between the upper and lower limbs. These results may suggest that the motor patterns stored in the central nervous system for quadrupedal locomotion may be retained through evolution and may still be exploited when humans perform such tasks.



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Increased alertness, better than posture prioritization, explains dual-task performance in prosthesis users and controls under increasing postural and cognitive challenge

Abstract

Sensorimotor impairments after limb amputation impose a threat to stability. Commonly described strategies for maintaining stability are the posture first strategy (prioritization of balance) and posture second strategy (prioritization of concurrent tasks). The existence of these strategies was examined in 13 below-knee prosthesis users and 15 controls during dual-task standing under increasing postural and cognitive challenge by evaluating path length, 95% sway area, and anterior–posterior and medial–lateral amplitudes of the center of pressure. The subjects stood on two force platforms under usual (hard surface/eyes open) and difficult (soft surface/eyes closed) conditions, first alone and while performing a cognitive task without and then with instruction on cognitive prioritization. During standing alone, sway was not significantly different between groups. After adding the cognitive task without prioritization instruction, prosthesis users increased sway more under the dual-task than single-task standing (p ≤ 0.028) during both usual and difficult conditions, favoring the posture second strategy. Controls, however, reduced dual-task sway under a greater postural challenge (p ≤ 0.017), suggesting the posture first strategy. With prioritization of the cognitive task, sway was unchanged or reduced in prosthesis users, suggesting departure from the posture second strategy, whereas controls maintained the posture first strategy. Individual analysis of dual tasking revealed that greater postural demand in controls and greater cognitive challenge in prosthesis users led to both reduced sway and improved cognitive performance, suggesting cognitive–motor facilitation. Thus, activation of additional resources through increased alertness, rather than posture prioritization, may explain dual-task performance in both prosthesis users and controls under increasing postural and cognitive challenge.



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Muscular responses appear to be associated with existence of kinesthetic perception during combination of tendon co-vibration and motor imagery

Abstract

The afferent inputs from peripheral sensory receptors and efferent signals from the central nervous system that underlie intentional movement can contribute to kinesthetic perception. Previous studies have revealed that tendon vibration to wrist muscles elicits an excitatory response—known as the antagonist vibratory response—in muscles antagonistic to the vibrated muscles. Therefore, the present study aimed to further investigate the effect of tendon vibration combined with motor imagery on kinesthetic perception and muscular activation. Two vibrators were applied to the tendons of the left flexor carpi radialis and extensor carpi radialis. When the vibration frequency was the same between flexors and extensors, no participant perceived movement and no muscle activity was induced. When participants imagined flexing their wrists during tendon vibration, the velocity of perceptual flexion movement increased. Furthermore, muscle activity of the flexor increased only during motor imagery. These results demonstrate that kinesthetic perception can be induced during the combination of motor imagery and co-vibration, even with no experience of kinesthetic perception from an afferent input with co-vibration at the same frequency. Although motor responses were observed during combined co-vibration and motor imagery, no such motor responses were recorded during either co-vibration alone or motor imagery alone, suggesting that muscular responses during the combined condition are associated with kinesthetic perception. Thus, the present findings indicate that kinesthetic perception is influenced by the interaction between afferent input from muscle spindles and the efferent signals that underlie intentional movement. We propose that the physiological behavior resulting from kinesthetic perception affects the process of modifying agonist muscle activity, which will be investigated in a future study.



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Central not peripheral vestibular processing impairs gait coordination

Abstract

Gait coordination is generated by neuronal inter-connections between central pattern generators in the spinal cord governed by cortical areas. Malfunction of central vestibular processing areas generates vestibular symptoms in the absence of an identifiable peripheral vestibular system lesion. Walking in the dark enforces a coordinated afference primarily from the vestibular and somatosensory systems. We hypothesized that patients with aberrant central vestibular processing would demonstrate unique gait characteristics, and have impaired gait coordination compared with those patients with abnormal peripheral vestibular function and healthy controls. One-hundred and eighteen subjects were recruited. Peripheral vestibular function was determined based on laboratory and clinical examinations. Patients with abnormal central vestibular processing had normal peripheral vestibular function. Subjects were instructed to walk at a comfortable pace during three visual conditions; eyes open, eyes open and closed intermittently, and eyes closed. Both patient groups showed a similar spatiotemporal gait pattern, significantly different from the pattern of the healthy controls. However, only the central vestibular patient group had an abnormal coordination of gait as measured by the phase coordination index (PCI). There were no significant interactions between the groups and walking conditions. Peripheral vestibular deficits impair gait though our data suggest that it is the central processing of such peripheral vestibular information that has a greater influence. This impairment may be related to a neural un-coupling between the brain and central pattern generator of the spinal cord based on the abnormal PCI, which seems to be a good indicator of the integrity of this linkage.



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The effects of a two-step transfer on a visuomotor adaptation task

Abstract

The literature has shown robust effects of transfer-of-learning to the contralateral side and more recently transfer-of-learning effects to a new effector type on the ipsilateral side. Few studies have investigated the effects of transfer-of-learning when skills transfer to both a new effector type and the contralateral side (two-step transfer). The purpose of the current study was to investigate the effects of two-step transfer and to examine which aspects of the movement transfer and which aspects do not. Individuals practiced a 30° visual rotation task with either the dominant or non-dominant limb and with either the use of the fingers and wrist or elbow and shoulder. Following practice, participants performed the task with the untrained effector type on the contralateral side. Results showed that initial direction error and trajectory length transferred from the dominant to the non-dominant side and movement time transferred from the elbow and shoulder condition to the wrist and finger conditions irrespective of which limb was used during practice. The results offer a unique perspective on the current theoretical and practical implications for transfer-of-learning and are further discussed in this paper.



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Comments on: When neuroscience gets wet and hardcore: neurocognitive markers obtained during whole body water immersion



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Role of point of application of perturbation in control of vertical posture

Abstract

The role of point of application of perturbation in the anticipatory (APAs) and compensatory (CPAs) postural control was studied. Twelve healthy participants stood on a sliding board (that was either locked and as such motionless or unlocked and as such free to move in the anterior–posterior direction). The body perturbations were applied either to the shoulders (by a pendulum impact) or the feet (by the movement of the sliding board). Electromyographic activity (EMG) of the trunk and lower extremity muscles was recorded. Latencies, integrals of EMG and muscle co-contraction (C) and reciprocal (R) activation indices were calculated and analyzed within the intervals typical for the APAs and CPAs. Higher EMG integrals were seen in the APAs phase when perturbation was applied to the shoulders. Reciprocal activation of muscles was seen in the APAs phase in the shoulders perturbation condition, while co-contraction was seen in the feet perturbation condition. Co-contraction was observed within the CPA phase in both experimental conditions. Higher C values were found in the feet perturbation condition in the CPA phase. The results suggest that different motor control strategies are employed by the central nervous system when encounter perturbations of similar magnitude but applied to different parts of the body. The outcome highlights the importance of investigation of the role of the point of application of the perturbation.



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Peg-manipulation capabilities during a test of manual dexterity differ for persons with multiple sclerosis and healthy individuals

Abstract

Manual dexterity declines with advancing age and the development of neurological disorders. Changes in manual dexterity are frequently quantified as the time it takes to complete the grooved pegboard test, which requires individuals to manipulate 25 pegs. The manipulation of each peg involves four phases: selection, transport, insertion, and return. The purpose of the study was to compare the times to complete the four phases of manipulating each peg and the forces applied to the pegboard during peg selection and insertion in persons with multiple sclerosis (MS) and age- and sex-matched healthy adults. Multiple-regression models that could explain the variance in pegboard times for each group of participants were compared to assess the relative significance of the peg-manipulation attributes. The performance of 17 persons with MS (52.2 ± 8.3 years) was compared with 17 control subjects (52.2 ± 11.5 years). The grooved pegboard test was performed on a force plate. Pegboard times for the MS group (104 ± 40 s) were longer than those for the Control group (61 ± 15 s). Regression analysis indicated that the pegboard times for the MS group could be predicted by the time for the peg-selection phase (R 2 = 0.78), whereas the predictors for Control group (R 2 = 0.77) were the times for the peg-transport (partial r = 0.80) and selection (partial r = 0.58) phases. The variance in the time it took the MS participants to complete the grooved pegboard test was strongly related to the time required to select each peg, whereas the pegboard times for the Control subjects depended mostly on the duration of the transport phase but also on the time to select each peg.



http://ift.tt/2zog4Sn

Perceptuo-motor planning during functional reaching after stroke

Abstract

In healthy young adults, reaching movements are planned such that the initial grasp position on the object is modulated based on the final task goal. This perceptuo-motor coupling has been described as the end-state comfort effect. This study aimed to determine the extent to which visuo-perceptual and motor deficits, but not neglect, due to stroke impact end-state comfort measured as the grasp-height effect. Thirty-four older adults (17 controls, 17 chronic stroke) performed a functional goal-directed two-sequence task with each arm, consisting of reaching and moving a cylindrical object (drain plunger) from an initial to four target platform heights, standardized to body height, in a block randomized sequence. Arm motor impairment (Fugl-Meyer Assessment) and visual–perceptual deficits (Motor-Free Visual Perception Test) were assessed in stroke subjects, and arm and trunk kinematics were assessed in all subjects. The primary outcome measure of the grasp-height effect was the relationship between the grasp heights used at the home position and the final target platform heights. Mixed model analysis was used for data analysis. The grasp-height effect was present in all participants, but decreased in stroke subjects with visuo-perceptual impairments compared to controls. In stroke subjects with sensorimotor impairments alone, indicated by altered kinematics, the grasp-height effect was comparable to controls. This first study examining the grasp-height effect in individuals with stroke provides new knowledge of the impact of visuo-perceptual deficits on movement planning and execution, which may assist clinicians in selecting more effective treatment strategies to improve perceptuo-motor skills and enhance motor recovery.



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Granger causality supports abnormal functional connectivity of beta oscillations in the dorsolateral striatum and substantia nigra pars reticulata in hemiparkinsonian rats

Abstract

Synchronized oscillatory neuronal activity in the beta frequency range has been reported in the basal ganglia (BG) of patients with Parkinson disease (PD) and PD animal models. The coherent abnormal oscillatory activities in the dorsolateral striatum (dStr) and substantia nigra pars reticulata (SNr) that accompany parkinsonian states have not been resolved. In this study, we recorded local field potentials (LFPs) in the dStr and SNr of 6-hydroxydopamine (6-OHDA)-induced dopamine (DA)-lesioned rats in an awake, resting state. Analyses of power spectral density and coherence data demonstrated augmented LFP power in the 24–36-Hz (high beta) range in both the dStr and SNr together with increased dStr–SNr coherence in the 24–36-Hz range, relative to sham controls; both effects were reversed by levodopa (l-dopa) treatment. Partial Granger causality analysis revealed a dStr→SNr propagation directionality of these beta oscillations. These findings support the involvement of increased synchronization of high beta activity in the dStr and the SNr, and suggest that dorsolateral striatal activity plays a determinant role in leading the coherent activity with the SNr in the development of parkinsonian pathophysiology.



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Arterial Lines Part 2

Part 2 on Art Lines

EMCrit by Scott Weingart.



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EMS credits WhatsApp with aiding in faster heart attack response

The messaging app is used to send diagnostic electrocardiograms directly to hospital cath labs

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Dallas officials reassure city that 911 problems are fixed

After two families claimed deaths due to 911 issues, Assistant Dallas Police Department Chief David Pughes said he is confident it will not happen again

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Pediatric population-specific disaster management

As we face more and different disasters, communities must consider the special needs of the pediatric portion that makes up one quarter of the population

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Ohio seeks technology ideas to solve national opioid crisis

Officials launched an $8 million effort to attract ideas for using technology to solve the national opioid addiction crisis that has touched scores of families

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International Regulations and Recommendations for Utility Data for Health Technology Assessment

Abstract

Recommendations and guidelines for the collection, generation, source and usage of utility data for health technology assessment (HTA) vary across different countries, with no international consensus. Many international agencies generate their own guidelines providing details on their preferred methods for HTA submissions, and there is variability in both what they recommend and the clarity and amount of detail provided in their guidelines. This article provides an overview of international regulations and recommendations for utility data in HTA for a selection of key HTA countries: Australia, Canada, France, Germany, the Netherlands, Spain (Catalonia), Sweden and the UK (England/Wales and Scotland). International guidelines are typically clear and detailed for the selection of countries assessed regarding the source description of health states (e.g. generic preference-based measure) and who should provide preference weights for these health states (e.g. general population for own country). Many guidelines specify the use of off-the-shelf generic preference-based measures, and some further specify a measure, such as EQ-5D. However, international guidelines are either unclear or lack detailed guidance regarding the collection (e.g. patients report own health), source (e.g. clinical trial) and usage (e.g. adjusting for comorbidities) of utility values. It is argued that there is a need for transparent and detailed international guidelines on utility data recommendations to provide decision makers with the best possible evidence. Where this is not possible it is recommended that best practice should be used to inform the collection, source and usage of utility values in HTA.



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The Identification, Review and Synthesis of Health State Utility Values from the Literature

Abstract

Systematic literature reviews of health-related quality of life (HRQoL) evidence that are to inform economic models can be challenging due to the volume of hits identified in searches using generic terms for HRQoL. Nevertheless, a robust review of the literature is required to ensure that the health state utility values (HSUVs) used in the economic model are the most appropriate available. This article provides a synopsis of literature relating to identifying, reviewing and synthesising HSUVs. The process begins with scoping the needs of the economic model, including the definitions of health states and the requirements of any reimbursement agencies. A sequence of searches may be required as the economic model evolves. The terminology used for HRQoL measures may be problematic, and as there is no robust HRQoL filter [equivalent to that applied for randomised control trial (RCTs)], sifting the results of sensitive searches can be resource intensive. Alternative approaches such as forward and backward citation searches may reduce the resources required, while maintaining the integrity of the search. Any included studies should be assessed in terms of quality using a recommended checklist, and insufficient detail in the primary studies should be noted as a short-coming in this exercise. Subject to homogeneity (similar populations, same measure and preference weights) evidence can be pooled in some way, although methodological research into the appropriateness of alternative techniques for meta-analysis is in its infancy. Reporting standards are key and as a minimum should include details on searches, inclusion/exclusion criteria (together with rationale for exclusion at each stage), assessment of quality and relevance of included studies, and justification for the choice of final HSUVs.



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Estimating Health State Utility Values for Comorbidities

Abstract

A comorbidity is defined as the presence of at least one additional health condition co-occurring with a primary health condition. Decision analytic models in healthcare depict the typical clinical pathway of patients in general clinical practice and frequently include health states defined to represent comorbidities such as sequelae or adverse events. Health state utility values (HSUVs) are often not available for these and analysts generally estimate them. This article provides a summary of the methodological literature on estimating methods frequently used together with worked examples. The three main methods used (minimum, multiplicative and additive) can produce a wide range in the values estimated. In general, the minimum method overestimates observed HSUVs and the magnitude of error tends to increase as the observed values decrease. Conversely, the additive and multiplicative methods generally underestimate observed values and the magnitude of the errors is generally greater for the additive method. HSUVs estimated using the multiplicative method tend to decrease for lower HSUVs and the largest errors are in observed HSUVs >0.6. Differences in estimated values can produce substantial differences in the resulting incremental cost effectiveness ratio. Based on the current evidence, the multiplicative method is advocated but additional research is required to determine appropriate methods when estimating values for additional comorbidities.



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Recommended Methods for the Collection of Health State Utility Value Evidence in Clinical Studies

Abstract

A conceptual model framework and an initial literature review are invaluable when considering what health state utility values (HSUVs) are required to populate health states in decision models. They are the recommended starting point early within a research and development programme, and before development of phase III trial protocols. While clinical trials can provide an opportunity to collect the required evidence, their appropriateness should be reviewed against the requirements of the model structure taking into account population characteristics, time horizon and frequency of clinical events. Alternative sources such as observational studies or registries may be more appropriate when evidence describing changes in HSUVs over time or rare clinical events is required. Phase IV clinical studies may provide the opportunity to collect additional longitudinal real-world evidence. Aspects to consider when designing the collection of the evidence include patient and investigator burden, whom to ask, the representativeness of the population, the exact definitions of health states within the economic model, the timing of data collection, sample size, and mode of administration. Missing data can be an issue, particularly in longitudinal studies, and it is important to determine whether the missing data will bias inferences from analyses. For example, respondents may fail to complete follow-up questionnaires because of a relapse or the severity of their condition. The decision on the preferred study type and the particular quality of life measure should be informed by any evidence currently available in the literature, the design of data collection, and the exact requirements of the model that will be used to support resource allocation decisions (e.g. reimbursement).



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Special Edition on Utility Measurement, PharmacoEconomics



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Sourcing and Using Appropriate Health State Utility Values in Economic Models in Health Care



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The Use of Mapping to Estimate Health State Utility Values

Abstract

Mapping functions are estimated using regression analyses and are frequently used to predict health state utility values (HSUVs) in decision analytic models. Mapping functions are used when evidence on the required preference-based measure (PBM) is not available, or where modelled values are required for a decision analytic model, for example to control for important sociodemographic variables (such as age or gender). This article provides an overview of the latest recommendations including pre-mapping considerations, the mapping process including data requirements for undertaking the estimation of mapping functions, regression models for estimating mapping functions, assessing performance and reporting standards for mapping studies. Examples in rheumatoid arthritis are used for illustration. When reporting the results of mapping standards the following should be reported: a description of the dataset used (including distributions of variables used) and any analysis used to inform the selection of the model type and model specification. The regression method and specification should be justified, and as summary statistics may mask systematic bias in errors, plots comparing observed and predicted HSUVs. The final model (coefficients, error term(s), variance and covariance) should be reported together with a worked example. It is important to ensure that good practice is followed as any mapping functions will only be as appropriate and accurate as the method used to obtain them; for example, mapping should not be used if there is no overlap between the explanatory and target variables.



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A Review of Generic Preference-Based Measures for Use in Cost-Effectiveness Models

Abstract

Generic preference-based measures (GPBMs) of health are used to obtain the quality adjustment weight required to calculate the quality-adjusted life year in health economic models. GPBMs have been developed to use across different interventions and medical conditions and typically consist of a self-complete patient questionnaire, a health state classification system, and preference weights for all states defined by the classification system. Of the six main GPBMs, the three most frequently used are the Health Utilities Index version 3, the EuroQol 5 dimensions (3 and 5 levels), and the Short Form 6 dimensions. There are considerable differences in GPBMs in terms of the content and size of descriptive systems (i.e. the numbers of dimensions of health and levels of severity within these), the methods of valuation [e.g. time trade-off (TTO), standard gamble (SG)], and the populations (e.g. general population, patients) used to value the health states within the descriptive systems. Although GPBMs are anchored at 1 (full health) and 0 (dead), they produce different health state utility values when completed by the same patient. Considerations when selecting a measure for use in a clinical trial include practicality, reliability, validity and responsiveness. Requirements of reimbursement agencies may impose additional restrictions on suitable measures for use in economic evaluations, such as the valuation technique (TTO, SG) or the source of values (general public vs. patients).



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The Role of Condition-Specific Preference-Based Measures in Health Technology Assessment

Abstract

A condition-specific preference-based measure (CSPBM) is a measure of health-related quality of life (HRQOL) that is specific to a certain condition or disease and that can be used to obtain the quality adjustment weight of the quality-adjusted life-year (QALY) for use in economic models. This article provides an overview of the role and the development of CSPBMs, and presents a description of existing CSPBMs in the literature. The article also provides an overview of the psychometric properties of CSPBMs in comparison with generic preference-based measures (generic PBMs), and considers the advantages and disadvantages of CSPBMs in comparison with generic PBMs. CSPBMs typically include dimensions that are important for that condition but may not be important across all patient groups. There are a large number of CSPBMs across a wide range of conditions, and these vary from covering a wide range of dimensions to more symptomatic or uni-dimensional measures. Psychometric evidence is limited but suggests that CSPBMs offer an advantage in more accurate measurement of milder health states. The mean change and standard deviation can differ for CSPBMs and generic PBMs, and this may impact on incremental cost-effectiveness ratios. CSPBMs have a useful role in HTA where a generic PBM is not appropriate, sensitive or responsive. However, due to issues of comparability across different patient groups and interventions, their usage in health technology assessment is often limited to conditions where it is inappropriate to use a generic PBM or sensitivity analyses.



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Heath State Utility Values for Cost-Effectiveness Models



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The Use of Health State Utility Values in Decision Models

Abstract

Methodological issues of how to use health state utility values (HSUVs) in decision models arise frequently, including the most appropriate evidence to use as the baseline (e.g. the baseline HSUVs associated with avoiding a particular health condition or event), how to capture changes due to adverse events and how to appropriately capture uncertainty in progressive conditions where the expected change in quality of life is likely to be monotonically decreasing over time. As preference-based measures provide different values when collected from the same patient, it is important to ensure that all HSUVs used within a single model are obtained from the same instrument where ever possible. When people enter the model without the condition of interest (e.g. primary prevention of cardiovascular disease, screening or vaccination programmes), appropriate age- and gender-adjusted HSUVs from people without the particular condition should be used as the baseline. General population norms may be used as a proxy if the exact condition-specific evidence is not available. Individual discrete health states should be used for serious adverse reactions to treatment and the corresponding HSUVs sourced as normal. Care should be taken to avoid double counting when capturing the effects for both less severe adverse reactions (e.g. itchy skin rash or dry cough) and more severe adverse events (e.g. fatigue in oncology). Transparency in reporting standards for both the justification of the evidence used and any 'adjustments' is important to increase readers' confidence that the evidence used is the most appropriate available.



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